Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia (TRS), only 40% of people with TRS respond, and there is limited evidence for augmentation agents. Cannabidiol (CBD) reduces positive symptoms in individuals with schizophrenia, but no trials have specifically examined its efficacy in those with clozapine-resistant schizophrenia.

To examine the clinical efficacy of CBD augmentation in people with clozapine-resistant schizophrenia.

This is a 12-week randomised, placebo-controlled, double-blind, parallel-group trial (registration number: ACTRN12622001112752). We will recruit 88 individuals with clozapine-resistant schizophrenia, randomised (1:1) to 1000 mg daily CBD versus placebo. Eligible individuals will be aged between 18 and 64 years, fulfil DSM-IV criteria for schizophrenia or schizoaffective disorder, have a total PANSS (Positive and Negative Syndrome Scale) score ≥60, have received oral clozapine for at least 18 weeks and have a clozapine level of >350 ng/mL. Interim analyses will be conducted at 25, 50 and 75% recruitment; these will also provide an opportunity to reallocate participants dependent on conditional power. The primary endpoint will be the difference in PANSS positive scores at the end of week 12. Secondary endpoints include depression, anxiety, sleep, quality of life, alcohol consumption, change in weight and metabolic syndrome components, and neurocognitive measures, as well as safety and tolerability.

Novel treatments for clozapine-resistant schizophrenia are urgently needed. If found to be effective, CBD may have a role as a novel and safe adjunct to clozapine.

Despite proven effectiveness in refractory schizophrenia, clozapine remains underutilised, and it is important to understand potential reasons for this. This study’s aim was to examine in a National sample of Consultant Psychiatrists their knowledge of, attitudes and perceived barriers to clozapine use.

A novel questionnaire was designed and distributed by email to 275 Consultant Psychiatrists in Republic of Ireland.

Twenty-eight percent (n = 77) completed the survey, with 55% of respondents practicing for 15 or more years. Clinicians expressed confidence in managing clozapine treatment and side effects and were well aware of clozapine’s clinical effectiveness and guideline-based use. A majority indicated insufficient experience managing rechallenge and half expressed insufficient experience managing adverse events. Perceived patient factors were highlighted as barriers with 69% of respondents reporting patients’ concern about effectiveness and 50% regarding tolerability. Sixty-four percent (n = 40) indicated that a specialised/tertiary clozapine service would facilitate initiation, with 57% (n = 36) reporting less frequent blood monitoring would aid clozapine prescribing. A majority identified that access to dedicated staff (81%, n = 51) and dedicated day hospital services (84%, n = 53) would facilitate community initiation.

Consultants are familiar with clozapine use and related guidelines. Dedicated staff and facilities for clozapine use is one identified structural change to enhance clozapine prescribing in Ireland. Tertiary service or clinical advice service would assist in clozapine rechallenge cases or in managing significant adverse events. More structured patient education regarding clozapine effectiveness and professional development programmes focused on managing side effects and rechallenge may promote clozapine use.

A significant proportion of people with clozapine-treated schizophrenia develop ‘checking’ compulsions, a phenomenon yet to be understood.

To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS).

Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.

A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04–0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = −0.28, 95% CI −0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction.

We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians’ therapeutic decisions.

Genetic approaches are increasingly advantageous in characterizing treatment-resistant schizophrenia (TRS). We aimed to identify TRS-associated functional brain proteins, providing a potential pathway for improving psychiatric classification and developing better-tailored therapeutic targets.

TRS-related proteome-wide association studies (PWAS) were conducted on genome-wide association studies (GWAS) from CLOZUK and the Psychiatric Genomics Consortium (PGC), which provided TRS individuals (n = 10,501) and non-TRS individuals (n = 20,325), respectively. The reference datasets for the human brain proteome were obtained from ROS/MAP and Banner, with 8,356 and 11,518 proteins collected, respectively. We then performed colocalization analysis and functional enrichment analysis to further explore the biological functions of the proteins identified by PWAS.

In PWAS, two statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset, including CPT2 (PPWAS-ROS/MAP = 4.15 × 10−2 and PPWAS-Banner = 3.38 × 10−3) and APOL2 (PPWAS-ROS/MAP = 4.49 × 10−3 and PPWAS-Banner = 8.26 × 10−3). Colocalization analysis identified three variants that were causally related to protein expression in the human brain, including CCDC91 (PP4 = 0.981), PRDX1 (PP4 = 0.894), and WARS2 (PP4 = 0.757). We extended PWAS results from gene-based analysis to pathway-based analysis, identifying 14 gene ontology (GO) terms and the only candidate pathway for TRS, metabolic pathways (all P < 0.05).

Our results identified two protein biomarkers, and cautiously support that the pathological mechanism of TRS is linked to lipid oxidation and inflammation, where mitochondria-related functions may play a role.

Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.

We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.

One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita.

Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

Clozapine is highly effective in patients with treatment-resistant schizophrenia but, to ensure optimal clinical response it is important to optimize its use and this depends on adequate pharmacological monitoring.

Evaluate the therapeutic response rate according to clozapine plasma concentration.

It was a cross-sectional, retrospective and analytical study, carried out over a period of six months, in the F and A psychiatry departments of the Razi hospital in Tunis, including patients followed for treatment-resistant schizophrenia and receiving clozapine. We evaluated the response to clozapine using the Brief Psychiatric Rating Scale (BPRS).

The average age was 37.7 ± 9.4. The mean age of introduction of clozapine was 31 years and the mean time to its introduction was 9.3 years. Clozapine was administered as a single drug in 85% of cases. The mean dose of clozapine was 373 mg/day. The mean of clozapine plasma concentration was 386.5 ng/ml with a minimum of 89 ng/ml and a maximum of 913 ng/ml. The clinical response rate to clozapine was 25% with a BPRS good response threshold value of less than 35. Patients with clozapine levels above the conventional cut-off of 350 ng/ml (n=34) had a response rate of 34.6%. A response rate of 37% was observed in the group of patients with a clozapine plasma concentration interval of 200-350 ng/ml. There was no statistically significant difference in therapeutic response (p=0186)

Our study revealed a therapeutic response variation according to plasma clozapine concentration and showed the existence of a non-negligible and effective response rate.

No significant relationships.

Despite pharmacological advances in the treatment of schizophrenia, significant number of patients are still treatment-resistant. Clozapine is recommended as first-line treatment for treatment-resistant schizophrenia (TRS) in guidelines. Despite the greater efficacy of clozapine over other antipsychotics in the management of TRS, a significant number of patients fail to attain adequate response or develop adverse effects, and more interventions are needed.

To describe a clinical case of treatment-resistant schizophrenia patient with prominent negative symptoms treated with combination of clozapine, cariprazine and fluoxetine, and to review the literature.

Clinical case presentation through review of the clinical file and non-systematic review on PubMed and ResearchGate.

A 41 year old female patient presented to inpatient clinic with low mood, occasional commanding and commenting verbal hallucinations, occasional suicidal thoughts, blunted affect, anhedonia, asociality, she was apathetic, lacked motivation to get up from bed, had night’s sleep disturbance. Patient was diagnosed with Schizophrenia in 2009, she has been hospitalized in Psychiatric wards for 16 times. She has received treatment with combinations of several antipsychotic drugs and antidepressants, had side-effects and have not reached full remission. During treatment with clozapine (up to 175mg per day) in combination with cariprazine (up to 4.5mg per day) and fluoxetine (up to 20mg per day), gradually negative symptoms decreased, patient became more active, showed interest in daily and rehabilitation activities, night’s sleep improved.

Patient with treatment-resistant schizophrenia benefited from combination of clozapine, cariprazine and fluoxetine. Further research is necessary on treatment combination strategies for TRS.

No significant relationships.

Treatment-resistant schizophrenia (TRS) and non-TRS may be associated with different dopaminergic and glutamatergic regulations. The concept of dysregulated glutamatergic concentrations in specific brain regions remains controversial. Herein, we aimed to assess (i) the distribution of the glutamatergic concentration in the brain, (ii) the association between working memory (WM) differences in TRS and non-TRS patients, and (iii) whether an alteration in the glutamate (Glu) level is associated with WM.

The participants included 38 TRS patients, 35 non-TRS patients, and 19 healthy controls (HCs), all of whom underwent 1.5-Tesla proton magnetic resonance spectroscopy of anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC). The ratios of glutamatergic neurometabolites to N-acetylaspartate + N-acetyl aspartylglutamate (NAAx) were calculated. Cognitive function was assessed using the Wechsler Adult Intelligence Scales, 4th Edition, which included the working memory index (WMI).

The TRS patients had a higher glutamate + glutamine (Glx)/NAAx ratio compared to the non-TRS patients and HCs in the ACC, but this was not significantly different in the MPFC. WM was negatively correlated with Glx/NAAx in the ACC among the non-TRS patients, but not in the TRS patients or HCs.

Our findings were consistent with most studies indicating that the glutamatergic concentration in the ACC plays important roles in the classification of TRS and cognition. Our results may provide potential evidence for predictors and treatment response biomarkers in TRS patients. Further research is needed to probe the value using the relationship between Glu and WM as a potential prognostic predictor of schizophrenia.

Treatment-resistant schizophrenia (TRS) affects 30% of people with a diagnosis of schizophrenia, and is defined as nonresponse to at least two trials of antipsychotic medication of adequate dose and duration. Clozapine is the only evidence-based treatment for TRS. Cariprazine may be considered significantly more efficacious than risperidone in improving negative symptoms of schizophrenia.

To describe the experience of using cariprazine in combination with clozapine in patients with refractory schizophrenia and negative symptoms.

Qualitative design. We present a case report study of a 47-year-old male with a diagnosis of TRS, treated in our outpatient mental health clinic for twenty years. The patient experiences crystallized delusional ideas of harm, self-referential, paranoid and mystical-messianic content, phenomena of theft and thought reading, egodistonic auditory hallucinations. No substance use disorder was observed. He made several suicide attempts in the context of intense suffering and psychotic anguish. Clozapine 400mg/day was instituted after no response to treatment with amisulpride, paliperidone, olanzapine or aripiprazole. The intensity of positive symptoms was reduced (experiences of damage, commenting and insulting auditory hallucinations, self-referentiality), as well as the emotional and behavioral repercussions. Persistent negative symptoms appeared such as apathy, abulia, clinophilia, anergy, social isolation, affective flattening, impairing his functionality.

Neuroimaging and periodic blood tests results were normal. Oral cariprazine was added in ascending doses up to 4.5mg with good tolerance. The patient showed remission of apathy, enhancement of behavioral activation, socialization and motivation to perform occupational activities.

Combinations of clozapine with partial agonists may improve the quality of life in refractory schizophrenia.

No significant relationships.

Of those with schizophrenia, one third develop treatment-resistant illness. Nearly 60% of these benefit from clozapine- the only antipsychotic medication licensed in this group.

As treatment-resistant illness developed in the follow-up of a first-episode psychosis (FEP) cohort, clozapine was prescribed. This study retrospectively compared the clozapine prescribing patterns, within this cohort, to National Institute for Health and Care Excellence (NICE) guidelines. In addition, impact on hospitalisation, physical health monitoring and augmentation strategies employed following clozapine initiation were examined. Factors delaying initiation of clozapine treatment or contributing to its discontinuation were also explored.

The study included 339 individuals resident within an Irish community mental health team catchment area, referred with FEP from 1 January 2005 to 31 August 2016. Data were extracted from electronic medical records.

Within the cohort, clozapine was prescribed to 32 individuals (9.4%). The mean number of adequate trials of antipsychotic prior to starting clozapine was 2.74 (SD 1.13; range 1–5). The mean time to clozapine trial was 2.1 years (SD 1.95; range 0.17–6.25). Following initiation of clozapine, mean hospital admissions per year fell from 2.3 to 0.3 (p=0.00). Mean inpatient days pre- and post-clozapine also decreased (147 vs. 53; p=0.00). In all, 18 patients ceased use of clozapine, 5 temporarily and 13 permanently.

Patients are being prescribed clozapine earlier than previously demonstrated. However, delayed treatment remains common, and many patients discontinue clozapine. Further research is necessary to describe and address factors which contribute to its discontinuation.

No significant relationships.

Clozapine can be a life-saving and course-altering treatment for patients with psychosis, particularly treatment-resistant schizophrenia. Unfortunately, clozapine monotherapy rarely leads to a full symptomatic remission.

This talk outlines key decision points in the use of clozapine: how to select patients for clozapine treatment and how to optimize clozapine’s efficacy in patients with a poor response to an adequate clozapine monotherapy trial.

Clozapine’s main indication is for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) should be used to optimize clozapine dosing during a clozapine trial and to rule-out pseudo-resistance. Up to 50% of patients do not respond to clozapine monotherapy and augmentation strategies can be utilized in such cases. Pharmacological add-on treatments are selected based on the most prominent symptom cluster (refractory psychosis, negative symptoms, depression and suicidality, aggression). Electroconvulsive therapy is the most effective augmentation strategy for refractory psychosis and suicidality. Non-pharmacological interventions and a focus on quality of life become important considerations in clozapine non-responders.

Clozapine is an important and underutilized tool in the management of treatment-resistant schizophrenia. It should be offered timely, as soon as treatment-resistance becomes apparent. Clinicians can use personalized augmentation strategies as part of a comprehensive treatment plan in order to achieve improvements even in patients with a poor response to clozapine alone. However, polypharmacy should be used judiciously, keeping in mind medical morbidity and quality of life.

I have the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution);

Treatment-resistant schizophrenia (TRS) is associated with high levels of functional impairment, healthcare usage and societal costs. Cross-sectional studies may overestimate TRS rates because of selection bias.

We aimed to quantify TRS rates by using first-episode cohorts to improve resource allocation and clozapine access.

We undertook a systematic review of TRS rates among people with first-episode psychosis and schizophrenia, with a minimum follow-up of 8 weeks. We searched PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews, and meta-analysed TRS rates from included studies.

Twelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1–27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5–30.0%, P < 0.001) among first-episode schizophrenia cohorts. Subgroup sensitivity analyses by location of recruitment, TRS definition, study quality, time of data collection and retrospective versus prospective data collection did not lead to statistically significant differences in heterogeneity. In a meta-regression, duration of follow-up and percentage drop-out did not significantly affect the overall TRS rate. Men were 1.57 times more likely to develop TRS than women (95% CI 1.11–2.21, P = 0.010).

Almost a quarter of people with first-episode psychosis or schizophrenia will develop TRS in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third. These high rates of TRS highlight the need for improved access to clozapine and psychosocial supports.

Routine therapeutic drug monitoring in clozapine therapy has previously not been considered justifiable. Using observational data, the clinical utility of annual clozapine assay monitoring is explored within a large mental health trust.

After the introduction of routine monitoring, the rate of clozapine assays rose to 2.3 per patient per year, with a consistent reduction in high-risk clozapine assays (<0.1 mg/L or >1.0 mg/L or any result more than 24 months old). High-risk assays are associated with a mortality rate of 31.6 deaths per 1000 patients, more than twice that of those within the target range (0.35–0.60 mg/L and conducted within the past 12 months) (P = 0.048).

Routine clozapine assay monitoring has significant clinical utility. Our simple but targeted approach can be readily implemented to reduce the number of patients with high-risk clozapine assay levels, potentially reduce all-cause mortality and provide optimal treatment for those with treatment-resistant schizophrenia.

Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non–treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values.

TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB’s Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05.

We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC.

Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored.

This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period.

Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication.

Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14–1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11–1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling.

Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.